Project Summary/Abstract Hidradenitis Suppurativa (HS) is a chronic debilitating inflammatory skin disease. Despite its high prevalence and morbidity, HS is understudied, and there is currently no uniformly effective treatment for this condition. Elucidation of disease pathogenesis, target identification and evaluation of novel treatments has been limited by the lack of comprehensive studies examining the immunology of this disease. This is compounded further by the fact that there are currently no animal models that accurately recapitulate the findings seen in HS skin. We have assembled a multi- disciplinary team of investigators at UCSF to better understand the immunopathogenesis of HS at both the cellular and molecular levels. This is centered around the recently established 'UCSF Hidradenitis Suppurativa Center of Excellence' (HSCE), a clinic dedicated entirely to providing first-rate care for HS patients and performing translational studies in this disease. With the HSCE, my laboratory has made significant advances in our understanding of the immunology of HS, including new observations of defects in the regulatory T cell (Treg) compartment. Tregs normally reside around hair follicles and regulate both neutrophilic inflammation and dermal fibrosis, two pathologic hallmarks of HS skin. Our preliminary results suggest that Tregs are both quantitatively and qualitatively defective in skin of HS patients. We hypothesize that dysfunctional Treg-mediated control of Th17 immune responses plays a central role in the pathogenesis of HS and that correcting this imbalance will effectively ameliorate inflammation and restore tissue immune homeostasis. Experiments outlined in this proposal will functionally dissect the cellular and molecular mechanisms controlling the Treg/Th17 balance in HS skin. We have developed an innovative ex vivo immune cell assay using HS skin. In addition, we have begun to establish a humanized mouse model of HS that recapitulates the inflammatory infiltrate observed in diseased skin of these patients. In these newly established model systems, we will utilize a novel molecule that preferentially binds to the high affinity IL-2 receptor to functionally determine if selective Treg augmentation attenuates inflammation in HS skin. In addition, we have recently discovered two cell surface receptors preferentially expressed on Tregs in human skin, CD27 and OX40, that play a major role in inhibiting Th17 differentiation in these cells. In separate experiments, we will determine whether inhibiting Th17 differentiation in Tregs via signaling through CD27 and/or OX40 restores immune balance in HS. The experiments outlined in this proposal represent a conceptually and technically innovative, comprehensive, and multidisciplinary approach to elucidate how functional manipulation of the Treg/Th17 differentiation axis influences inflammation in HS skin. The Th17 pathway in human skin has primarily been studied in psoriasis and several therapeutic approaches developed for psoriasis are now being considered for HS. Thus, the results of the studies proposed herein are both timely and relevant, in our attempts to better understand the pathogenesis of HS and determine whether immune pathways targeted in psoriasis may or may not translate to this disease.